Abstract
OBJECTIVE: Fibroblast growth factor 21 (FGF21) is a metabolic regulator of glucose and lipid metabolism. The physiological role of FGF21 is not yet fully elucidated, however, administration of FGF21 lowers blood glucose in diabetic animals. Moreover, increased levels of FGF21 are found in obese and diabetic rodents and humans compared with lean/non-diabetic controls. METHODS: Adult male rhesus macaque monkeys were chronically maintained on a high-fat diet (HFD) or a standard diet (control, CTR). Plasma levels of FGF21, triglycerides and cholesterol were measured and body weight was record. Glucose-stimulated insulin secretion (GSIS) and glucose clearance was determined during an intravenous glucose tolerance test. Furthermore, expression of FGF21 and its receptors were determined in liver, pancreas, three white adipose tissues (WATs) and two skeletal muscles. RESULTS: A cohort of the high-fat fed monkeys responded to the HFD with increasing body weight, plasma lipids, total cholesterol, GSIS and decreased glucose tolerance. These monkeys were termed HFD sensitive. Another cohort of monkeys did not become obese and maintained normal insulin sensitivity. These animals were defined as HFD resistant. Plasma FGF21 levels were significantly increased in all HFD fed monkeys compared with the CTR group. The HFD-sensitive monkeys showed a significant increase in FGF21 mRNA expression in all examined tissues compared with CTR, whereas FGF21 expression in the HFD-resistant group was only increased in the liver, pancreas and the retroperitoneal WAT. In the WAT, the co-receptor β-klotho was downregulated in the HFD-sensitive monkeys compared with the HFD-resistant group. CONCLUSION: This study demonstrates that HFD changes FGF21 and FGF21 receptor expression in a tissue-specific manner in rhesus monkeys; differential regulation is moreover observed between HFD-sensitive and -resistant monkeys. Monkeys that maintain normal levels of the FGF21 co-receptor β-klotho in the WAT on HFD were protected toward development of dyslipidemia and hyperglycemia.